The objectives of the proposed research are: 1) to study the relationship between the concentration of cardiac cyclic AMP and myocardial contractility as influenced by calcium flux into the heart, 2) to clarify the mechanism responsible for the impaired negative chronotropic response to vagal stimulation in hyperthyroid rats. Special emphasis will be given to a study of the metabolism of choline as affected by thyroid hormones. The isolated perfused rat heart will be used to measure changes in cyclic AMP and force of contraction in response to alterations in transmembrane movement of calcium. Use of specific antagonists to the transport of calcium, such as verapamil, will enable us to investigate the immediate and prolonged effects of reduced calcium influx on cardiac function and metabolism. Additonal studies will be done to determine the effects of verapamil on calcium turnover and total calcium content in the heart. In the studies concerned with action of the thyroxine on parasympathetic regulation of the heart, we shall use the open-chest rat preparation. To verify the hyperthyroid state, cardiovascular measurements will be made prior to obtaining samples of blood for determination of plasma choline dehydrogenase activity. A detailed investigation of choline metabolism, breakdown as well as synthesis, in hyperthyroid rats should provide information to explain the mechanism whereby choline infusion into thyrotoxic animals restores to normal the negative chronotropic response to vagal stimulation. BIBLIOGRAPHIC REFERENCES: Shanfeld, J., M.E., Hess and N.R. Levine: Effects of verapamil on myocardial contractility, cardiac adenosine 3',5'-monophosphate and heart phosphorylase. J. Pharmacol. Exp. Ther. 193: 317-326, 1975. Hess, M.E.: Effects of verapamil on ventricular contractility, cardiac rate and myocardial cyclic AMP. Sixth International Congress of Pharmacology, 1975.